Pulmonary Gas Exchange in Severe Chronic Asthma Response to 1000/0 Oxygen and Salbutamol 1 - 4

EUGENI BALLESTER, 5 JOSEP ROCA, LWIS RAMIS, PETER D. WAGNER, and ROBERT RODRIGUEZ-ROISIN

Introduction

Ventilation-perfusion (VA/Q) inequality is the major mechanism of gas exchange abnormalities found in bronchial asthma. However, it has been shown that correlates with clinical conditions and spirometry are poor (1, 2). An almost constant feature previously reported in patients with asthma has been the presence of a considerable amount of blood flow through poorly ventilated lung units (lung units with VA/Q ratio lessthan 0.1 but greater than 0.005,which is the lowest value separable from zero, or true shunt). Shunt, on the other hand, is conspicuously absent (3, 4). The pattern of these VA/Q distributions may be influenced by such factors as the degree of airflow obstruction, response to bronchodilators, or the type of asthmatic subject studied. In general, recent studies using the multiple inert gas elimination technique in patients with acute severe asthma and severe airflow obstruction made by our group have shown substantial abnormalities in gas exchange and VA/Q inequality (5-7). On the other hand, chronically symptomatic patients with less airflow obstruction have shown only moderately altered VA/Q relationships (8, 9). The hypothesis behind the present study was that long-standing chronic severe airflow obstruction may induce changes in VA/Q distribution different from acute episodes. This could be related to chronic alveolar hypoxia with subsequent and sustained pulmonary vascular changes that might not be responsive to agents known to cause vasodilatation in the pulmonary circulation. We therefore sought patients with relatively severe chronic asthma without substantial spirometric remissions and examined their VA/Q relationships both after breathing 100010 O 2 and after inhaled salbutamol. 558

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SUMMARY Ventilation-perfusion (V Inequality has been evaluated using the multiple Inert gas technique In nine nonsmoking patients (mean ± SD, age 56 ± 10 yr) with stable, severe, chronic asthma (partially reversible airway obstruction; baseline FEV1, 39 ± 10% predicted) before and durIng 100% O2 breathing and then 15 min after three puffs (300 J1g) of Inhaled salbutamol. The aim of this stUdy was to investigate whether this type of asthma was associated with a different pattern of V inequality from that observed in acute episodes and In particular to determine whether pattern was fixed or could be altered by bronchodilator agents or O2 breathing. The prethe V distribution was broad and unimodal but without shunt (V 0) or dominant pattern of V areas (V < 0.1 to > 0.005). The amount of V Inequality as assessed by the disperlow V sion of the distribution of pulmonary bloodflow (log SDa) was not great (log Soo, o.n ± 0.09), and no correlation was found with the degree of airway obstruction, Pa02 or AaP0 2. During 100% Inequality worsened (from log SDa of o.n ± 0.09 to 1.11 ± 0.21, P 0.01) O 2 breathing, with an Increase In the perfusion of low V units (from 0.43 ± 0.66% to 6.3 ± 6.5%, P 0.02) but stili no development of shunt. This suggests the presence of hypoxic pulmonary vasoconstricrelationships. Inhaled salbutamol tion breathing air, possibly contributing to the preSElrvatlon of V relationships nor on Pa02. These findings may Improved FEV1 by 35%, but had no effect on reflect preferential distribution of the aerosol to those pulmonary areas already well ventilated or, alternatively, no effect of salbutamol on those abnormalities responsible for the gas exchange defects.

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AM REV RESPIR DIS 1990; 141:558-562

Methods Subject Selection Nine nonsmoking patients with stable but severe chronic asthma were recruited from the outpatient clinic.Anthropometric data on the nine patients are presented in table 1.All were women, with a mean age of 56 ± 10 yr (range, 40 to 69 yr, mean ± SO). They were selected on the basis of a prolonged history of chronic asthma with the following characteristics: (1) presence of long-standing severe airway obstruction evaluated through repeated spirometry, (2) a positive bronchodilator response but with the persistence of moderate to severe limitation of airflow on maximal bronchodilation, and (3) absence of clinical or chest radiographic evidence of any other disease. To further characterize these patients and differentiate them from those with chronic obstructive pulmonary disease (COPO), static lung volumes and DLeo data obtained from six of the nine patients in whom complete pulmonary function tests were performed showed, in percent predicted, TLC = 101070, FRC = 136070, RV = 141070, and OLeo = 101070 (in the three others, body plethysmography and OLeo measurements could not be accurately assessed because of the severi-

ty of airway obstruction). All patients were receiving regularly an inhaled beta-2 agonist (salbutamol), beclomethasone dipropionate with or without oral theophylline. All nine patients required oral steroids (10 to 20 mg daily on average)for the control of their symptoms. At the time of the study, all patients

(Received in original form October 25, 1988 and in revised form March 27, 1989) 1 From the Departments of Medicine, Servei de Pneumologia, Hospital Clinic, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; and the Section of Physiology, University ofCalifornia, San Diego, La Jolla, California. 1 Supported by Grant No. CCA830918S from the Joint U.S.-Spain Committee and Grant No. PA8S-0016 from the Comisi6n de Investigaci6n de Ciencia y Tecnologia (CICYT). 3 Presented in part at the Annual Meeting of the American Thoracic Society, New Orleans, May 1987. 4 Correspondence and requests for reprints should be addressed to Robert Rodriguez-Roisin, M.D., Servei de Pneumologia, Hospital Clinic, Villarroel 170, 08036-Barcelona, Spain. 5 Former Research Fellow of Fundaci6 BOSCH i GIMPERA, Universitat de Barcelona.

559

VENTILATION.PERFUSION INEQUALITY IN CHRONIC ASTHMA

TABLE 1 ANTHROPOMETRIC DATA AND BASELINE SPIROMETRY Patient No.

Age

1 2 3 4 5 6 7 8 9 Mean ± SO

50 59 65

(yr)

er

58 69 48 40 49 56 10

FVC

VE

FE'4

PEFR

FEF 2s - 7s

Weight (kg)

Height (em)

RR (min-1)

VT (L)

(Llmin)

(L)

(0/0 pred)

(L)

(0/0 pred)

(LIs)

(0/0 pred)

(LIs)

(0/0 pred)

82 52 62 86 68

161 147 143 155 159 150 153 153 148 152 6

14 14 21 12 10 11 22 18 24 16 5

0.54 0.37 0.47 0.48 0.60 0.57 0.41 0.42 0.34 0.47 0.09

7.50 5.20 9.82 5.53 6.00 6.23 8.91 7.55 8.26 7.22 1.59

1.95 1.49 1.05 1.84 2.23 1.26 2.23 2.11 1.26 1.71 0.46

(57) (57) (33) (66)

0.98 0.64 0.59 1.26 0.86 0.65 1.04 1.09 0.78 0.9 0.2

(37) (33) (28) (63) (37) (36) (44) (42) (35) (39) (10)

0.42 0.24 0.20 0.90 0.27 0.27 0.41 0.45 0.45 0.40 0.21

(17) (14) (17) (56) (13) (19) (17) (16) (20) (21) (13)

2.71 1.82 1.60 2.71 2.56 0.98 3.42 1.74 1.30 2.09 0.79

(45) (35) (29) (52) (45) (20) (60) (29) (24) (38) (14)

er

64 59 76 68 11

Definition of abbreviations: RR = respiratory rate; VT capacity; PEFR = peak expiratory flow rate.

were symptomatic, with shortness of breath as the predominant symptom. Their mean FEV. was 39 ± 10070 and FEF25-75 was 21 ± 13070 of predicted values, respectively(10). The study was approved by the Hospital Clinic Investigation Committee, and oral consent was obtained from all participants.

Study Design Patients were studied at the same time of the day (between 10.00 A.M. and 1.00 A.M.). Preceding the study, usual doses of xanthine derivatives and beta-2 adrenergic agents were withheld for at least 24 and 8 h, respectively (11). Only oral steroids werecontinued according to the schedules of their physicians. Measurements were performed in a semirecumbent position while they breathed room air through a lowresistancevalve(No. 1500; Hans Rudolph, Kansas City, MO). The degree of VA/Q mismatch was evaluated breathing air, and also after 30 min of 100070 O 2 (in a random sequence). Further measurements were made after salbutamol inhalation (30 min was allowed for O2washout after 100070 O 2breathing prior to salbutamol administration and a further 15 min to sampling). Each set of measurements was made according to the following sequence: (1) heart rate and intravascular pressures, (2) simultaneous arterial blood and mixed expired gas sampling for inert and respiratory gas determinations, (3) cardiac output, and (4) forced spirometry. Salbutamol was administered in a series of three metered-dose aerosolized puffs (300 tJg) by the same observer and in the same manner in all patients.

Methodologic Aspects Spirometry. 'Iriplicate measurements of FEV., FVC, and peak expiratory flow rates (PEFR) (Datospir-2002; Siebel-Med, Barcelona, Spain) were made according to the ATS recommendations. Hemodynamic measurements. Theseincluded systemic arterial pressures and heart rate, which were continuously recorded through a four-channel recorder (HP-7754 B; Hewlett-

= tidal

volume;

(71) (50) (73) (65)

(44) (57) (13)

VE = minute

ventilation; FEF25- 75

Packard, Waltham, MA). Cardiac output (QT)was determined by the indicator-dilution method (5-mg bolus ofindocyanine green injected at the superior vena cava or the right atrium) (6). Tracingsof dye concentration versus time were derived from a densitometer used in conjunction with a DC-410 cuvette transducer (Waters Instruments, Rochester, NY) at the peripheral artery site. Arterial and expiredO2 and CO2 measurements. Arterial blood gas tensions (Pa02, Pac02)and pH were measured in blood sampled through an indwelling catheter inserted in the radial or brachial artery and measured in duplicate with an IL-1302 blood gas analyzer (Instrumentation Laboratories, Milano, Italy). Arterial P0 2 was corrected by temperature. The alveolar-arterial oxygen difference (AaP0 2)was calculated using the alveolar air equation, PAo2 = PI02 - (Pa.c0 2 / R) + Pa.c02 * FI02 (1 - R)/R), where PI02 = PI02 (PB - PH20) and R is the respiratory exchange ratio. Physiologic dead space (Vn/VT)was calculated according to the Bohr equation, Vn/VT = (Pae02 - PEe02)/Pae02' where PEe02 is mixed expired Pe02. Mixed expired gas samples for O2 consumption ('102) and CO 2 production (Ve02) measurements were collected at the end of a flow-through mixing chamber, fractional concentrations of mixed expired O 2and CO 2being measured in a mass spectrometer (Medishield, Multi-gas MS2; Ohmeda-BOC, London, UK). VAl Q relationships. These were determined using the multiple inert gas elimination technique of Wagner and coworkers (12). Infusion of a mixture of six inert gases with different solubilities(sulfurhexafluoride [SF6 ] , ethane, cyclopropane, enflurane, ether, and acetone) dissolved in saline was given at 3 to 5 ml/min through a peripheral vein. Steadystate conditions were assured by monitoring end-tidal Pe02, respiratory frequency, tidal volume, heart rate, and systemic arterial pressures. Duplicates of arterial blood and mixed expired gas samples were obtained, and concentration of inert gases were measured using a modified gas chromatograph (HP 5880 A;

= forced

expiratory flow at midrange of vital

Hewlett-Packard) previously described (1315). Mixed venous inert partial pressures of each inert gas were calculated from arterial and expired gases using the Fick principle. Minute ventilation ('IE) and respiratory rate were measured minute by minute through a previously calibrated Wright spirometer attached at the end of the mixing box. Results ofVAlQ indices are the mean of the duplicates.

Statistics Results are expressed as mean ± SD. Comparisons between baseline values and those after either 100070 O 2or salbutamol were analyzed using Wilcoxon signed rank test for paired observations. When appropriate, correlations were analyzed using Pearson's correlation coefficient of linear regression analysis. The p level of significance was < 0.05.

Results

Baseline Findings As shown in tables 1 to 3, mean FEV 1 was 0.88 ± 0.23 L (range, 0.6 to 1.3 L), which represents a mean percent predicted value of 39070. Mean heart rate (HR) and systemic arterial pressures werewithin normal range. Cardiac output (QT)was not increased (4.79 ± 0.92 L/min), and cardiac index was normal (2.89 ± 0.39 Lzmin/m"). Mean VE was 7.2 ± 1.6 L/min and V02 was 218 ± 40 ml/min. Mean Pa02 was slightly lower than normal (77.2 ± 7.1 mm Hg) and more than 70 mm Hg in all but one patient, whereas Paoo, was in the normal range (38.8 ± 2.1 mm Hg; range, 36.1 to 41.5 mm Hg), Both mean AaPo2and mean VD/VT (Bohr) were slightly increased, at 25.9 ± 6.5 mm Hg and 39 ± 0.1070 (178 ± 37 ml/breath), respectively. The VA/Q distributions werecharacterized by and large by a broad unimodal bloodflow VA/Q distribution. Verylittle perfusion was associated with low VA/Q units (VA/Q